This portion of the program project grant is focused on the molecular circuitry that underlies the function of the subsets of neurons that specifically express the Mrg family of GPCRs. The intracellular events triggered by ligand activation of receptor are ultimately reflected in the function and phenotype of the animal. Thus, we will further characterize the ligands that interact with the MrgA, MrgB, MrgC, and MrgD receptors and their homologues. We will establish the nature and molecular role of the specific macro-molecules that respond to and regulate receptor function in each of the different Mrg-expressing cell types. We will design and generate mutations and genetic constructs that change the activity of specific signaling molecules associated with the Mrg system. Together with our colleagues in this Program Project we will study the effects of these perturbations on molecular, cellular and animal phenotypes. The remarkable specificity of expression of the Mrg receptors in subsets of cells that have been associated with the perception of pain suggest that they play a role in neuropathic pain and associated disease. The comprehensive picture of the Mrg system provided by this program project grant will lead to a better understanding of pain perception and eventually to the development of novel treatments for disorders associated with pain.